Some compounds exhibiting alpha adrenergic activity are well known in the art. It is also generally known and accepted in the art that those compounds may be used for the treatment of a wide variety of diseases and conditions of the peripheric system and the central nervous system (CNS).
The alpha adrenergic receptors can be divided on a pharmacological basis into alpha1- and alpha2-adrenoceptors, which can both be further divided into subtypes. Three genetically encoded subtypes, namely alpha2A-, alpha2B- and alpha2C-adrenoceptors, have been discovered in human. Accordingly, alpha2-adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha2A-, alpha2B- and alpha2C-adrenoceptors. A fourth, pharmacologically defined subtype, alpha2D, is known in rodents and in some other mammals, and it corresponds to the genetically defined alpha2A-adrenoceptors.
The alpha2-adrenoceptor subtypes have distinct tissue distributions and functional roles. For instance, while alpha2A-adrenoceptors are widely expressed in various tissues, alpha2C-adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of specific CNS-mediated behavioural and physiological responses.
Compounds that are non-specific to any of the above-mentioned alpha2 subtypes, and compounds that are specific to certain alpha2 subtypes, are already known. For example, atipamezole is a non-specific alpha2 antagonist. Atipamezole has been described in, for example, EP-A-183 492 (cf. p. 13, compound XV) and Haapalinna, A. et al., Naunyn-Schmiedeberg's Arch. Phannacol. 356 (1997) 570-582. U.S. Pat. No. 5,902,807 describes compounds that are selective antagonists for the alpha2C subtype and may be used in the treatment of mental illness, e.g. mental disturbance induced by stress. Such compounds include, for example, MK-912 and BAM-1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha2B- or 2B/2C-adrenoceptors. In addition, WO 01/64645 relates to derivatives of quinoline useful as alpha2 antagonists, as well as to selective alpha2C antagonist agents. The disclosures of all documents cited above in this paragraph are incorporated by reference herein.
Several arylquinolizine derivatives and related compounds have been described in the literature, some of which possess valuable pharmaceutical effects. For example, U.S. Pat. Nos. 4,806,545 and 4,044,012 describe 1,1-disubstituted indolo[2,3-a]quinolizidines useful as vasodilators and antihypoxic agents. Further, substituted arylquinolizine derivatives, described for example in U.S. Pat. No. 4,686,226 possessing alpha2-adrenoceptor antagonistic activity are useful for example as antidepressant, antihypertensive, or antidiabetic agents or platelet aggregation inhibitors. In addition, U.S. Pat. No. 3,492,303 relates to indolo[2,3-a]quinolizidines useful as central nervous system depressants. Molecular modelling of targets for synthesis of alpha1A and alpha2 selective ligands is discussed in Griffith, R. et al., J. Comput.-Aided Mol. Design 13 (1999) 69-78.